Abstract

Immunological tolerance refers to a reduction or complete inhibition of the ability of an individual to mount a specific immune
response upon immunisation. Several mechanisms are involved in induction and maintenance of tolerance, including clonal deletion,
clonal anergy, receptor editing, receptor down‐modulation and lymphocyte sequestration. The number of antigen presenting cells,
the number and activity of regulatory T cells and regulatory B cells, the nature and amount of antigenic peptides generated
and the presence of co‐stimulatory signals in a particular tissue are also important. Depending on the site and the level
of antigen expression, different states of peripheral B‐cell and T‐cell tolerance can be reached. In certain situations, they
could act in an additive manner. In humans, induction of immunological tolerance is an important issue in both transplantation
biology and autoimmune diseases, and present research aims at designing novel strategies to induce specific tolerance.

Key Concepts:

Tolerance induction is easier in animals with an immature immune system or with a mature immune system that has been compromised
by irradiation, drugs or thoracic drug drainage.

In general, when a given antigen is used over a wide range of concentrations, intermediate doses induce immunity, and low
and high doses induce tolerance.

The introduction route is a key variable in tolerance induction, particularly in adult animals, presumably by determining
the accessibility of the antigen to professional antigen presenting cells.

The tolerant state is not absolute and tolerance is rarely complete. With time, it gradually wanes and eventually disappears,
but it can be deliberately terminated by several means.

Persistence of the tolerogen in the periphery and its accessibility to the immune system are generally required to maintain
tolerance, which continuously inactivates newly emerging T and B cells that develop in lymphoid organs.

T lymphocytes specific for self‐peptides bound to major histocompatibility complex peptides are eliminated by clonal deletion,
a process known as negative selection. Similarly, self‐reactive B cells are purged from the functional repertoire during the
transition from the pre‐B to mature B‐cell stage in the bone marrow.

Anergy is a functionally silent state induced in B cells and T cells, allowing them to persist functionally inactivated in
tolerant animals.

Receptor editing is a form of receptor processing that markedly alters the variable region genes expressed by B cells and,
consequently, changes the specificity of the surface immunoglobulin and maintains B‐cell tolerance to self.

Two functional lymphocyte subsets, called regulatory T cells and regulatory B cells, have recently been found to contribute
to the maintenance of the fine equilibrium required for immune tolerance.

In humans, induction of immunological tolerance in the adult is an important issue in both transplantation biology and autoimmune
diseases, and present research aims at designing novel strategies to induce specific tolerance.

High‐ and low‐dose tolerance. When a given antigen is used over a wide range of concentrations, intermediate doses induce immunity, and low and high doses induce tolerance.

Figure 2.

Clonal deletion. The fate of B lymphocytes is governed by the specificity of their receptors. Encounter of a self‐reactive B cell with an autoantigen leads to its physical elimination by apoptotic death. By contrast, a nonautoreactive B cell will persist in the primary repertoire and can engage in an immune response against a potential threat.

Figure 3.

Clonal anergy. In this tolerance mechanism, a self‐reactive B cell encountering its target autoantigen will undergo a state of functional silencing, but will persist in the immune repertoire. Upon receiving additional B cell engagement in the presence of T lymphocyte help, the anergic B cell can regain a functional state and become a member of the lymphocyte repertoire.

Figure 4.

Receptor editing. Upon encounter with a self‐antigen, the autoreactive B cell initiates a series of successive Ig gene rearrangements that lead to expression of a new Ig cell surface receptor. As a result, the B cell will extinguish its autoreactivity, acquire a new specificity and persist in the immune repertoire.

Nossal GJ and
Pike BL
(1980)
Clonal anergy: persistence in tolerant mice of antigen‐binding B lymphocytes incapable of responding to antigen or mitogen.
Proceedings of the National Academy of Sciences of the USA
77:
1602–1606.